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PMCOL 343 > Glucocorticoids > Flashcards

Glucocorticoids Flashcards

1
Q

Which response does the HPA axis mediate?

A

stress response

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2
Q

Which structures does the HPA axis involve?

A

hypothalamus, anterior pituitary gland, adrenal gland

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3
Q

What is the stimulus for HPA axis?

A

physical, psychological, environmental stressors

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4
Q

Provide an overview of the HPA axis using the hormones involved.

A

stressor –> CRH –> POMC –> ACTH

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5
Q

Which hormone potentiates the effects of CRH?

A

vasopressin (AVP)

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6
Q

What is the action of ACTH on the adrenal cortex?

A

regulate production of steroid hormones

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7
Q

main physiological glucocorticoid

A

cortisol

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8
Q

main physiological mineralocorticoid

A

aldosterone

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9
Q

Which physiological steroid hormone is produced in the zona fasciculata? Which enzymes are involved?

A
  • cortisol
  • 17-alpha-hydroxylase, 21-beta-hydroxylase, 11-beta-hydroxylase
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10
Q

Which physiological steroid hormone is produced in the zona glomerulosa? Which enzymes are involved?

A
  • aldosterone
  • 21-beta-hydroxylase, 11-beta-hydroxylase
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11
Q

Which physiological steroid hormone is produced in the zona reticularis? Which enzymes are involved?

A
  • androstenedione
  • 17-alpha-hydroxylase
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12
Q

which layer of the adrenal cortex is the only layer that remains functional in the absence of pituitary function?

A

zona glomerulosa

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13
Q

primary stress hormone

A

cortisol

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14
Q

What are 3 modes of physiological regulation of the HPA axis?

A
  1. diurnal rhythm in basal steroidogenesis (i.e. rhythmic regulation)
  2. negative feedback regulation by adrenal steroids
  3. changes in steroidogenesis in response to stress
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15
Q

Describe the rhythmic regulation of the HPA axis.

A
  • cortisol secreted in pulsatile, ultraradian rhythm
  • also circadian rhythm in females along the estrous cycle
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16
Q

Describe the normal circadian rhythm of the HPA axis.

A
  • 1) circadian signals from SCN clock genes propagate to hypothalamic nuclei
  • 2) light-dark signals to SCN influence HPA –> cortisol production
  • 3) GC peak at 8 AM = start of active cycle
  • 4) nadir levels during sleeping = inactive phase
  • 5) adrenal glands receive sympathetic autonomic innervation –> reduced responsiveness to ACTH during inactive phase
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17
Q

Where does GC negative feedback occur in the HPA axis? Where do endogenous GCs induce neg feedback? exogenous?

A
  • hypothalamus = endogenous target
  • pituitary = exogenous target
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18
Q

How do GCs inhibit CRH secretion in negative feedback regulation of the HPA axis?

A

direct effects on hypothalamic CRH neurons

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19
Q

How do GCs inhibit ACTH secretion in negative feedback regulation of the HPA axis?

A
  • rapid response: inhibit response of corticotrophs to CRH via GR
  • delayed response: suppress POMC expression via GR
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20
Q

primary target for negative feedback when GC levels are elevated?

A

GR

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21
Q

Describe the regulation of GC secretion in acute stress response.

A
  • stress (fight/flight response) overrides normal negative feedback control mechanisms
  • ACTH increase –> cortisol increases as ACTH falls to basal level
  • pulsatility maintained
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22
Q

Which plasma proteins are GCs bound to, in order to keep them inactive?

A
  • 90% CBG
  • 10% albumin
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23
Q

which enzyme activates bound GCs in the liver?

A

11-beta-HSD1

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24
Q

which enzyme inactivates bound GCs in the kidney?

A

11-beta-HSD2

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25
Q

What are the 2 GRs and what is the difference between the 2?

A
  • GR-alpha: transactivation/repression
  • GR-beta: inhibit GR-alpha signal
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26
Q

Describe GC-GR signaling in direct DNA interaction.

A
  • GRalpha DIMER bind to GRE –> direct transactivation
  • GRalpha DIMER bind to nGRE –> direct transrepression
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27
Q

Describe GC-GR signaling in composite GRE binding.

A

GRalpha MONOMER binds to GRE –> recruit co-activators / co-repressors (for transactivation / transrepression)

28
Q

Describe GC-GR signaling in tethering.

A

GRalpha MONOMER interacts with another TF without contacting DNA –> enhance/decrease capacity of TF to bind DNA and recruit co-regulators

29
Q

What are some non-genomic effects of GCs?

A
  • chaperone protein signaling
  • protein-protein interaction
30
Q

effects of cortisol in muscle

A

catabolic (fatty acid oxidation, proteolysis, decrease glucose uptake)

31
Q

effects of cortisol in pancreas

A
  • acute: stimulate insulin secretion and beta-cell growth
  • long-term: inhibit insulin synthesis/secretion and induce beta-cell apoptosis
32
Q

effects of cortisol in heart? permissive or direct?

A
  • vasoconstriction and increase BP
  • permissive effects on catecholamines and Ang II
33
Q

effects of cortisol in kidneys? permissive or direct?

A
  • decrease vasopressin secretion and effects
  • permissive
34
Q

effects of cortisol on the brain?

A
  • sleep
  • appetite
  • memory
  • cognition
  • emotion
  • excessive cortisol linked to major depressive disorders
35
Q

effects of cortisol in adipocytes?

A
  • increase lipolysis
  • increase lipid uptake
  • decrease glucose uptake
  • overall: INCREASE IN BODY FAT
36
Q

effects of cortisol in liver? permissive or direct?

A
  • increase gluconeogenesis, glycogenolysis, glycogen storage
  • leads to insulin resistance
  • permissive effects on glucagon and catecholamines
37
Q

What is the main difference between primary and secondary adrenal insufficiency?

A
  • primary: adrenal glands don’t make enough GC/MC
  • secondary: pituitary doesn’t make enough ACTH
38
Q

How does primary adrenal insufficiency lead to increased CRH and ACTH?

A

GC deficiency leads to loss of negative feedback on the pituitary and hypothalamus

39
Q

most common inherited form of primary adrenal insufficiency? Which enzyme is affected? How does it affect sex hormones?

A
  • congenital adrenal hyperplasia
  • 21-beta-hydroxylase
  • increased sex hormones
40
Q

What is the name for acquired primary adrenal insufficiency in adults?

A

Addison’s disease

41
Q

what is the mechanism of Addison’s disease?

A
  • destruction of adrenal cortex by T-cell mediated AUTOIMMUNE mechanisms
  • B cells in local lymph nodes produce AUTOANTIBODIES against 21-beta-hydroxylase
42
Q

Which adrenal insufficiency disease decreases aldosterone?

A

primary adrenal insufficiency

43
Q

What is another name for secondary adrenal insufficiency?

A

Cushing’s disease

44
Q

what is the most common cause of tertiary adrenal insufficiency?

A

exogenous administration of GCs

45
Q

which adrenal insufficiency disease is characterized by the following:

  • round, red, full face
  • buffalo hump
  • thin skin
  • excess body hair
  • central obesity
  • interrupted menstrual cycle
A

cushing’s syndrome

46
Q

Which hormone does Cushing’s mainly affect? How does it affects its levels? What is it caused by?

A

excess ACTH production (and increased cortisol) caused by pituitary tumor

47
Q

endogenously derived short acting GC drug

A

cortisol

48
Q

synthetically derived short acting GC drugs

A
  • prednisolone
  • methylprednisolone
49
Q

intermediate acting GC drug

A

triamcinolone

50
Q

long acting GC drugs

A
  • dexamethasone
  • betamethasone
51
Q

difference between potency of synthetic and endogenous GCs

A

synthetic = better activator of GR

52
Q

difference between specificity of synthetic and endogenous GCs

A

synthetic bind GR with HIGHER affinity and MR with lower affinity (than endogenous)

53
Q

oral pharmacokinetic considerations for GCs

A
  • effective
  • good for systemic treatment
54
Q

topical pharmacokinetic considerations for GCs

A
  • absorbed systemically
  • may cause HPA axis inhibition
  • inhaled for asthma and COPD
  • not appropriate for 11-keto GCs
55
Q

intravenous pharmacokinetic considerations for GCs

A
  • achieve high concentrations rapidly in targeted body fluids
  • good for systemic treatment
56
Q

intramuscular pharmacokinetic considerations for GCs

A
  • more prolonged effects
  • good for systemic treatments
57
Q

What is the purpose of GC replacement therapy? What are proposed therapies/drugs?

A
  • purpose: replicate circadian rhythm of cortisol secretion
  • drugs: chronocort and continuous subcutaneous hydrocortisone infusion (CSHI)
58
Q

What are some non-endocrine uses of GCs?

A
  • anti-inflammatory
  • immunosuppressive therapy
  • treat neoplastic disease
59
Q

What are GC mechanisms of action as anti-inflammatory agents?

A
  • inhibit transcription of pro-inflammatory gene –> reduce Cox2 –> reduce prostaglandins
  • inhibit transcription of pro-inflammatory gene –> reduce interleukins, interferon, tumor necrosis factor
  • promote transcription of anti-inflammatory gene –> annexin A1 –> inhibit PLA2 and leukocyte infiltration
60
Q

What are the 2 major drawbacks of GC therapy?

A
  • adverse effects: hypertension, diabetes mellitus, osteoporosis
  • GC resistance (inherited and acquired)
61
Q

What are the types of GC antagonists?

A
  • inhibitors of GC synthesis
  • GR antagonist
62
Q

list the following for ketoconazole:

  • class of GC antagonist
  • treat which disease
  • mechanism
  • side effects
A
  • class: inhibitor of GC synthesis
  • disease: Cushing’s
  • mechanism: inhibitor of 17-alpha-hydroxylase
  • side effects: increase in levels of progesterone and aldosterone
63
Q

list the following for metyrapone:

  • class of GC antagonist
  • treat which disease
  • mechanism
  • side effects
A
  • class: inhibitor of GC synthesis
  • disease: Cushing’s
  • mechanism: inhibitor of 11-beta-hydroxylase
  • side effects: hirsutism and hypertension
64
Q

list the following for mifepristone:

  • class of GC antagonist
  • mechanism
  • treatment for?
A
  • class: GR antagonist
  • mechanism: inhibit activation of GR
  • treats: ectopic ACTH secretion or adrenal carcinoma
65
Q

What is the goal of selective GR modulators (SGRM)?

A
  • amplify anti-inflammatory effects of GCs
  • minimize metabolic effects of GCs

PMCOL 343 (27 decks)

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